β₁- and β₂-adrenoceptor binding and functional response in right and left atria of rat heart

The properties of β₁- and β₂-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to β-adrenoceptor agonists were examined. [¹²⁵I](-)-pindolol (¹²⁵IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. The k₁'s for association in right and left atria were 6.5×10⁹ l/mol-min and 2.3×10⁹ l/mol-min respectively, while the k_-1's for dissociation were 0.20 min^-1 and 0.17 min^-1. The kinetically determined K_D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibrium K_D's determined from Scatchard analysis of saturation isotherms of specific¹²⁵IPIN binding. Inhibition of¹²⁵IPIN binding by β-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by β₁- and β₂-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by β₁-selective (practolol, atenolol and metoprolol) and β₂-selective (ICI 118,551) antagonists gave estimates of the proportion of β₁- and β₂-adrenoceptors present in rat atria. Right atria contained 67±4.2%β₂-adrenoceptors and 33±4.2%β₂-adrenoceptor, while left atria contained 67±2.8%β₁- and 33±2.8%β₂-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by β-adrenoceptor agonists were also measured. pA₂ values for non-subtype selective β-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with K_D values determined for specific¹²⁵IPIN binding. pA₂ values for β₁- and β₂-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the p K_D values of these drugs in binding to β₁-adrenoceptors, but not with the p K_D values in binding to β₂-adrenoceptors. Dose-response curves for stimulation of both rate and force by the β₂-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of β₁-adrenoceptors with metoprolol than by selective blockade of β₂-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating β₁-adrenoceptors. These results suggest that β₁- and β₂-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2:1 ratio, however only β₁-adrenoceptors mediate the chronotropic and inotropic effects of β-adrenoceptor agonists.